1. Field of the Invention
This invention relates to novel cyanoaziridines for treatment of cancer. 2. Description of Related Art
This invention is directed towards aziridine-1-carboxamides related to imexon having improved anti-tumor activity.
The search for compounds having anti-tumor activity has included 2-cyanoaziridines with substituents on the nitrogen atom. German patent 2,736,296 (Feb. 22, 1979) claimed 2-cyanoaziridines and its derivatives. German patent 2,727,550 (Jan. 4, 1979) claimed 2-cyanoaziridines with substituted carbonyl, sulfonyl, or phosphoryl groups on nitrogen. East German patent 110 492 (Dec. 20, 1974) claimed 2-cyanoaziridines with alkanoyl and aroyl substituents on nitrogen. It also claimed 2-cyanoaziridine-1-carboxamide. The cyclization of 2-cyanoaziridine-1-carboxamide to imexon, as well as imexon itself, was claimed in U.S. Pat. No. 4,083,987 (Apr. 11, 1978). Two German patents, 2,740,248 (Mar. 15, 1979) and 2,656,323 (Jun. 15, 1978) claimed the preparation of 2-cyano-1-phenoxycarbonylaziridine and its conversion into 2-cyanoaziridine-1-carboxamide. Immunosuppressive activity for imidazolidine derivatives related to imexon was claimed in U.S. Patent 4,996,219.
Imexon (4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one) was developed by Bicker (Immune Modulation and Control of Neoplasia by Adjuvant Therapy, M. A. Ghirigos, Ed., Raven Press, New York, 1978, p. 389) in an investigation of cyanoaziridine derivatives with potential cancerostatic action. It is a cyclic isomer of 2-cyanoaziridine-1-carboxamide, from which it is formed by treatment with a catalytic amount of KOH in methanol as illustrated below (U. Bicker, W. Kampe, and W. Steingross, U.S. Pat. No. 4,083,987, Apr. 11, 1978).
Imexon has both direct cytotoxicity to tumor cells and immunomodulatory effects. It is active against a variety of human tumor cell lines in culture and against fresh human tumor cell lines in clonogenic assay. It is selectively cytotoxic to multiple myeloma in the clonogenic assay (S. E. Salmon and E. M. Hersh, J. Natl. Cancer Inst., 86, 228, 1994). Imexon is active against a variety of transplanted tumors in rodents (U. Bicker and G. Hebold, IRCS Med. Sci.: Cancer; Hematology; Immunology and Allergy; Pharmacology, 5, 428, 1977; U. Bicker and P. Fuhse, Exp. Path. Bd. 10, S. 279-284, 1975) and it is active against human lymphoma, melanoma, and prostate cancer cell lines in SCID mice (Hersh, et al., Proc. Am. Assoc. Cancer Res., 36, 294, 1995). Objective responses were observed in dogs with mast cell tumors after treatment with imexon (R. T. Dorr, J. D. Liddil, M. K. Klein, and E. M. Hersh, Invest. New Drugs, 13, 113, 1995). Despite the presence of an aziridine ring, imexon is not myelosuppressive, which makes it potentially valuable in combination chemotherapy.